Relationships over time between health and physiological measures of stress are still poorly understood. A role in health has been highlighted for the hypothalamic- pituitary-adrenal (HPA) axis, which produces the stress hormone cortisol. However, existing studies have generally investigated this system at a single time-point, which prevents understanding of which comes first: altered HPA axis function or the health outcomes associated with it. Longitudinal research is needed following individuals over years to understand how this physiological system both affects, and is affected by, mood, health and well-being. Cortisol levels are tightly regulated via a process known as negative feedback: cortisol turns off its own production, thus quickly reining in cortisol levels after an increase. Individuals vary in their degree of negative feedback, depending on their glucocorticoid sensitivity: in other words, how well their brains can detect and respond to cortisol. Interestingl, major depression is associated with lower than average glucocorticoid sensitivity and HPA negative feedback. There is also evidence that negative feedback is not a static trait but can change within an individual over time, e.g. when the depression resolves. It is not yet known, though, whether alterations in negative feedback occur first, and lead to development of mood or other health problems, and/or whether mood or health status cause changes in the degree of negative feedback. It is also completely unknown how negative feedback is associated with changes in mood, life stress, health and well- being beyond psychological disease states such as depression. This project addresses these questions by adding measurement of HPA axis negative feedback to the rich longitudinal data on mood, stress, and health in the Notre Dame Study of Health and Well-Being (NDHWB). A bi- directional model is hypothesized, in that a person's degree of negative feedback both impacts and is impacted by their health and well-being. The project has two goals (Aims) related to this bi-directional model. Aim 1 is to understand which individual difference variables and contextual factors in the preceding 5 years of NDHWB data precede or predict differences in negative feedback. Aim 2 is to investigate which present and future health and well-being measures are associated with or predicted by negative feedback. To test these Aims, 150 participants ranging in age from 18 to 90 will be selected from the NDHWB study to assess HPA axis negative feedback. This is measured by degree of suppression of an upstream hormone, ACTH, caused by an injection of a low dose of cortisol (compared to a control day with no cortisol injection.) Negative feedback data will be combined with the NDHWB study's multiple years of data on individual differences, life stress, daily stressors, mood, and health outcomes. This will provide an unprecedented opportunity to discover time-course relationships between stress, mood, and dysregulation in the HPA axis. This knowledge is of vital importance for understanding the development of well-being and resilience against illness across the lifespan. PUBLIC HEALTH RELEVANCE: Findings from this project will increase our understanding of how life experiences and emotions alter stress physiology over time, and in turn, how stress physiology affects future mental and physical health. The goal of this project is to collect nuanced information about the HPA axis (an important physiological stress system) in the context of an ongoing longitudinal study, which examines stressful life experiences, mood, physical health, and other aspects of well-being over several years, in people of different ages. This project thus has the potential to yield important insights about the physiological underpinnings of how stress and mood affect health across the lifespan.